Risk of chemotherapy-induced febrile neutropenia in intermediate-risk regimens: Clinical and economic outcomes of granulocyte colony-stimulating factor prophylaxis

BACKGROUND: Chemotherapy-induced neutropenia increases the risk of febrile neutropenia (FN) and infection with resultant hospitalizations, with substantial health care resource utilization (HCRU) and costs. Granulocyte-colony stimulating factor (GCSF) is recommended as primary prophylaxis for chemotherapy regimens having more than a 20% risk of FN. Yet, for intermediate-risk (10%-20%) regimens, it should be considered only for patients with 1 or more clinical risk factors (RFs) for FN. It is unclear whether FN prophylaxis for intermediate-risk patients is being optimally implemented. OBJECTIVE: To examine RFs, prophylaxis use, HCRU, and costs associated with incident FN during chemotherapy. METHODS: This retrospective study used administrative claims data for commercial and Medicare Advantage enrollees with nonmyeloid cancer treated with intermediate-risk chemotherapy regimens during January 1, 2009, to March 31, 2020. Clinical RFs, GCSF prophylaxis, incident FN, HCRU, and costs were analyzed descriptively by receipt of primary GCSF, secondary GCSF, or no GCSF prophylaxis. Multivariable Cox regression analysis was used to examine the association between number of RFs and cumulative FN risk. RESULTS: The sample comprised 13,937 patients (mean age 67 years, 55% female). Patients had a mean of 2.3 RFs, the most common being recent surgery, were aged 65 years or greater, and had baseline liver or renal dysfunction; 98% had 1 or more RFs. However, only 35% of patients received primary prophylaxis; 12% received secondary prophylaxis. The hazard ratio of incident FN was higher with increasing number of RFs during the first line of therapy, yet more than 54% of patients received no prophylaxis, regardless of RFs. Use of GCSF prophylaxis varied more by chemotherapeutic regimen than by number of RFs. Among patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine, and prednisone, 76% received primary prophylaxis, whereas only 22% of patients treated with carboplatin/paclitaxel received primary prophylaxis. Among patients with a first line of therapy FN event, 78% had an inpatient stay and 42% had an emergency visit. During cycle 1, mean FN-related coordination of benefits–adjusted medical costs per patient per month ($13,886 for patients with primary prophylaxis and $18,233 for those with none) were driven by inpatient hospitalizations, at 91% and 97%, respectively. CONCLUSIONS: Incident FN occurred more often with increasing numbers of RFs, but GCSF prophylaxis use did not rise correspondingly. Variation in prophylaxis use was greater based on regimen than RF number. Lower health care costs were observed among patients with primary prophylaxis use. Improved individual risk identification for intermediate-risk regimens and appropriate prophylaxis may decrease FN events toward the goal of better clinical and health care cost outcomes.


Implications for managed care pharmacy
Among 13,937 patients treated for nonmyeloid cancers with intermediaterisk chemotherapy, risk of FN rose as number of clinical RFs rose, but primary GCSF prophylaxis did not rise accordingly. Variation in prophylaxis was greater based on regimen than RF number. Lower health care resource utilization and costs were observed with prophylaxis use. Improved individual risk identification for intermediate-risk regimens and appropriate prophylaxis may decrease FN events, toward the goal of better clinical and cost outcomes.
A serious complication arising with myelosuppressive chemotherapy is neutropenia, which increases a patient's susceptibility to febrile neutropenia (FN) and serious infection often requiring costly hospitalization and treatment. 1,2 In addition to the life-threatening nature of FN itself, there are other sequelae such as increased health care resource utilization (HCRU) and costs required to prevent mortality (eg, hospitalization and antibiotics) and potential chemotherapy dose reductions or delays that may negatively affect outcomes for many types of cancer treatments. [3][4][5] Granulocyte-colony stimulating factors (GCSFs) are approved by the US Food and Drug Administration to decrease the incidence of FN following myelosuppressive chemotherapy administration, thereby reducing subsequent infections. Guidelines from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and the European Organization for Research and Treatment of Cancer (EORTC) recommend primary prophylactic GCSF for chemotherapy regimens with anticipated risk of FN more than 20% (high risk of FN). [6][7][8][9] Clinical trial data and economic modeling have established that for high-risk patients, primary prophylaxis dramatically lowers incidence of FN and investment in GCSF prophylaxis is mitigated by reduced hospitalization costs and overall positive societal value associated with reduced FN incidence. [10][11][12] However, for patients receiving chemotherapy associated with intermediate risk of FN (ie, regimens with FN incidence ranging from 10% to 20%), the NCCN guidelines do not recommend routine primary prophylaxis with GCSFs, but it may be considered in patients with at least 1 clinical risk factor (RF) for FN. Additionally, ASCO's "Choosing Wisely" campaign discourages the use of GCSF prophylaxis for patients receiving a chemotherapy regimen with less than a 20% risk of FN. 13 However, other studies call into question whether this threshold for primary prophylaxis is optimized for the best population-based outcomes. 14,15 In the era of value-based care, the reduction in GCSF prices due to the availability of biosimilars may allow the reinvestment of these savings to treat additional subpopulations of patients. For example, a recent economic analysis demonstrated that primary prophylaxis with biosimilar filgrastim was cost-effective in certain intermediate-risk scenarios. 16 Another economic model projected that practices that participate in the Oncology Care Model could realize improved outcomes and decreased costs if they expanded the number of patients who received GCSF prophylaxis. 11 Furthermore, the expanded use of primary prophylaxis in the intermediate-risk setting was recommended in the context of the COVID-19 pandemic, due to the high risk of morbidity and mortality among this patient group. 17 Because of these recent shifting dynamics, this study was performed to describe prophylaxis patterns, NCCN-defined FN RFs, and HCRU and costs among patients treated with chemotherapy regimens associated with intermediate risk for FN.

DATA SOURCE AND STUDY DESIGN
This retrospective observational study examined insurance claims data from US Commercial and Medicare Advantage enrollees with a nonmyeloid malignancy who received an intermediate-risk chemotherapy regimen. Deidentified data were obtained from the Optum Research Database, a proprietary database of administrative medical and pharmacy claims including data for more than 73 million people throughout the United States. Claims data were linked to mortality data from the Centers for Medicare & Medicaid and the Social Security Administration, in compliance with applicable US laws. No patients' identifiable data were extracted or accessed; thus, per US DHHS 45 C.F.R. Part 46, neither institutional review board approval nor waiver of authorization was required.

STUDY SAMPLE
The study sample was identified by the following inclusion criteria: (1) at least 1 claim for a systemic anticancer agent (Supplementary Table 1 and Supplementary Figure 1, available in online article) during a 10-year identification period (June 30, 2009, through December 31, 2019), the first date (doxorubicin hydrochloride), vincristine, and prednisone, 76% received primary prophylaxis, whereas only 22% of patients treated with carboplatin/paclitaxel received primary prophylaxis. Among patients with a first line of therapy FN event, 78% had an inpatient stay and 42% had an emergency visit. During cycle 1, mean FN-related coordination of benefits-adjusted medical costs per patient per month ($13,886 for patients with primary prophylaxis and $18,233 for those with none) were driven by inpatient hospitalizations, at 91% and 97%, respectively.
CONCLUSIONS: Incident FN occurred more often with increasing numbers of RFs, but GCSF prophylaxis use did not rise correspondingly. Variation in prophylaxis use was greater based on regimen than RF number. Lower health care costs were observed among patients with primary prophylaxis use. Improved individual risk identification for intermediate-risk regimens and appropriate prophylaxis may decrease FN events toward the goal of better clinical and health care cost outcomes.
Patients were also characterized by GCSF prophylaxis status, which we defined as having a claim for a GCSF within 4 days of chemotherapy receipt using published algorithms. 21 Any GCSF received outside of these time periods was considered treatment for neutropenia, rather than prophylactic use. Patients were stratified into the following different cohorts by GCSF prophylaxis strategy: primary (starting between cycle 1 start date to 4 days after), secondary (starting during cycles 2-6), or no prophylaxis (if none was observed during these time periods). Patients who received GCSF during days 5-21 of cycle 1 were considered to have GCSF treatment rather than prophylaxis.
Outcomes. FN events occurring in each cycle were identified from insurance claims using ICD-9 or ICD-10 codes (Supplementary Table 2) for neutropenia and fever, as previously described, 21 to calculate cumulative risk of FN. The FN-related HCRU (per patient per month [PPPM]) was calculated for ambulatory visits, emergency department (ED) visits, and inpatient admissions, all defined as attributable to FN if the claim was coded for neutropenia in position 1 or 2 or by facility claims for inpatient stays. Length of inpatient stays was also calculated. The PPPM medical costs were similarly calculated (including ambulatory, ED, inpatient, and other costs) and adjusted to 2019 US$ using the Consumer Price Index for Medical Care. 22 Costs were also adjusted to account for coordination of benefits for patients who may have been dually eligible for commercial and Medicare coverage. Payments from Medicare and other payers were estimated on the basis of coordination of benefits (COB) information obtained by the health plan in its usual course of business in order to report a total paid or allowable amount. 23

STATISTICAL ANALYSES
Descriptive analyses were conducted using SAS software version 9.4, with cohorts defined by receipt of primary GCSF, secondary GCSF, or no GCSF prophylaxis observed. Continuous data were summarized as mean, median, SD, and first and third quartiles, accounting for variable observation time (PPPM) as needed. Categorical data were presented as frequencies (percentages). Cox regression was used to examine the unadjusted association between number of clinical RFs present and cumulative risk of FN.

SAMPLE DESCRIPTION
Among 775,208 patients who received a systemic anticancer agent during the identification period, 13,937 were included in the analysis based on inclusion/exclusion criteria of which set the index date, and (2) at least 1 nondiagnostic claim for a nonmyeloid malignancy (lymphoid and solid cancers) (Supplementary Table 2), in any position, before the index date, during the identification period. Patients were required to be at least aged 18 years and have continuous health plan enrollment for a minimum of 9 months (from the pre-index baseline period of 6 months to a follow-up period of at least 3 months post-index). Patients were excluded by diagnoses codes indicative of same-site primary malignancies during baseline, myeloid malignancies, pregnancy, clinical trial participation, HIV, hematopoietic stem cell transplantation, surgery, or radiation during cycle 1, incomplete demographic information, incomplete cycle 1 regimen administration, FN during baseline or first 5 days of cycle 1, or a baseline claim for a GCSF (Supplementary Table 1 Intermediate-risk regimens were defined per NCCN guidelines except for docetaxel/pertuzumab/trastuzumab and docetaxel/trastuzumab regimens, which were not included in the NCCN guidelines but are considered to have intermediate risk according to clinical studies. 18,19

STUDY MEASURES
Baseline Patient Characteristics. Baseline patient demographic and clinical characteristics were studied. Demographic characteristics included age, sex, insurance type, and geographic region of residence as of the index date. Clinical characteristics measured during the baseline (ie, pre-index) included Charlson Comorbidity Index score, type of cancer diagnosed, and the following patient-specific FN RFs, based on NCCN definitions 20 : baseline radiation, baseline neutropenia, recent surgery, bone metastasis, liver dysfunction, renal dysfunction, and age of at least 65 years during the 6-month pre-index period.
Chemotherapy and Prophylaxis. The LOT1 chemotherapy regimen was identified for up to 6 cycles using a published algorithm. 21 The start of LOT1 was set as the first date of administration and/or fill of NCCN-recommended agent(s) (Supplementary Figure 1). The end date of a LOT was set as the earliest date of either receipt of a different agent or discontinuation of the first regimen defined by a predetermined gap in therapy following an expected run-out period. The length of the days' supply depended on the expected cycle length. The LOT could also have been censored at the date of the end of the study period, disenrollment from the health plan, or death (Supplementary Table 1).
( Figure 1). Significant differences were observed in most characteristics among patients grouped by receipt of GCSF prophylaxis, as described below.
Patient Characteristics. Among the 13,937 included patients, 35% received primary prophylaxis, 12% received secondary prophylaxis, and 54% had no prophylactic use of GCSF ( Table 1). The mean (SD) age of the overall sample was 67.4 (10.7), and 55% of patients were female. The mean ages of patients were significantly different among the primary prophylactic cohort vs the secondary and no prophylactic cohorts; those receiving primary prophylaxis were generally older (68.5, 66.3, and 67.0, respectively, P < 0.001). Female sex was observed among 53% of the primary prophylactic GCSF cohort vs 61% in the secondary prophylactic GCSF cohort and 55% in the no prophylactic GCSF cohort (P < 0.001).
The mean (SD) length of follow-up overall was 82.8 (63.5) days, with the secondary prophylaxis cohort having significantly longer follow-up (118. FN RFs. Across all patients, with all regimens and all types of cancer, the most common RF was surgery within 30 days before start of the regimen (84%), followed by age 65+ at index date (67%), liver dysfunction (31%), renal dysfunction (21%), bone metastases (12%), baseline radiation (10%), and baseline neutropenia (2%). Surgery, age 65+, and liver or renal dysfunction were the most common RFs across regimens (Supplementary Table 3 Whether or not patients received prophylactic GCSF, among all regimens, only 2% of patients did not have any RFs, and 20% had one RF (Supplementary Figure 2). The remaining 78% had 2 or more RFs. The mean number of FN RFs ranged between 1.5 and 2.6, depending on the specific regimen. The regimens used with patients having

TABLE 1 Demographic and Clinical Characteristics
The majority of patients diagnosed with non-Hodgkin lymphomas (99%) were treated with the RCHOP regimen; similarly, FOLFOX was primarily used to treat patients with colorectal cancer (96%), cisplatin/etoposide for patients with testicular cancer (98%), and docetaxel monotherapy for patients with prostate cancer (82%). The average LOT duration was 82.8 days overall. Excluding censored lines (ended due to the end of the study period or health plan disenrollment), the average was 80.2 days. The reasons for end of a LOT were surgery (33%), treatment discontinuation (19%), radiation (19%), switch to a new regimen (19%), death (7%), or insurance disenrollment (4%).
Prophylaxis Use by Regimen. The 3 most common regimens, carboplatin/paclitaxel, etoposide/carboplatin, and RCHOP, were used in 69% of the patient sample ( Figure 2). Patients treated with RCHOP had the largest proportion receiving GCSF prophylaxis, with 76% of patients receiving primary prophylaxis, whereas only 22% of patients treated Chemotherapy Regimens. The frequency of identified chemotherapy regimens, varying by cancer type, is shown in Supplementary Table 3

Discussion
Multiple studies have questioned whether current recommendations for GCSF prophylaxis optimizes outcomes for patients treated with intermediate-risk regimens. 14,15,24 Using real-world US data, we sought to describe prophylactic use of GCSF, patient FN RFs, and FN outcomes with the most prevalent intermediate-risk chemotherapy regimens for treatment of many types of cancer. As expected, the incidence of FN increased with the number of RFs across several cancer types and most commonly used regimens. Despite this, the overall number of patients receiving GCSF was not as high as expected and did not increase in proportion to the number of RFs. Analysis of FN-associated health care COB-adjusted PPPM costs supported the expectation that primary GCSF prophylaxis would be associated with reduced FN-related health care burden. Opportunities for better outcomes with primary prophylaxis, based on RFs and intermediate-risk regimens, are presented. It has long been established that the use of prophylactic GCSF lowers the risk of FN; yet GCSF prophylaxis has been reported as underused by observational studies since 2005. 24 As compared with the overall rate of 47% who received any prophylaxis in the current study (ranging from 2009 to 2020), the Schenfeld study reported that prophylactic GCSF use rose from 42% to 54% between 2005 and 2017. In the current study, 53% of patients did not receive any primary or secondary prophylactic GCSF; in fact, more than 50% of patients with 1 to 4+ individual RFs did not receive any prophylaxis. The results of the current study align with previous studies in that prophylaxis use was lower than expected with intermediate-risk with the most frequently observed regimen, carboplatin/ paclitaxel, received primary prophylaxis.

OUTCOMES
Risk Level and Incident FN. During all cycles of LOT1, unadjusted hazard ratios (HR) for FN rose with increasing number of RFs, with statistical significance at 3 RFs (HR = 3.1; P = 0.027) and 4 or more RFs (HR = 4.0; P = 0.007) ( Table 2). During the first cycle, the HR increased with each incremental increase in number of RFs; at 4 or more RFs, statistical significance was observed vs no RFs (HR = 3.5; P = 0.034) ( Table 2). FN-Related HCRU and Costs. The FN-related costs (for patients who completed a cycle 1 that included an FN event) by prophylactic use of GCSF are shown in Figure 3 and HCRU in Supplemental Figure 3. In the overall sample, 26% of patients had FN-related ambulatory visits, with outpatient visits among 13% of patients with no primary prophylaxis, and among 10% of those with primary prophylaxis. The proportion of patients with ED and inpatient visits in the primary and no primary prophylaxis cohorts was 46% and 36%, and 77% and 79%, respectively. However, inpatient stays were shorter for patients receiving primary prophylaxis with a mean (SD) 6.8 (6.7) days, whereas length of stay was 8.3 (8.8) days for patients with no primary prophylaxis. The FN-related PPPM statistics showed similar trends, albeit slightly augmented. Mean inpatient days PPPM were 8.9 (10.2) in the primary prophylactic GCSF use cohort and to 10.7 (11.7) in the no prophylactic GCSF use cohort. Similarly, higher medical COB-adjusted PPPM costs (driven by inpatient hospitalization costs) were observed among patients who did not receive primary GCSF prophylaxis.   and may be used to induce long-term remission (or cure) instead of palliative care. In this study, patients treated with RCHOP had the largest proportion of GCSF-treated patients with 76% receiving primary prophylaxis, whereas only 8% of patients treated with a similarly common regimen, FOLFOX, received primary prophylaxis. These findings are expected, as the risk for FN with RCHOP is greater than it is for FOLFOX. Further, it is well established that patients have the greatest chance for longterm remission when RCHOP is given at a high relative dose intensity (RDI) and that, historically, dose intensity has not been considered as important for FOLFOX. Thus, because RDI does matter for long-term response, dose reductions or delays used to prevent FN may yield suboptimal outcomes.
In such cases, greater use of primary GCSF prophylaxis appears prudent, especially in an era when GCSF costs continue to drop. 25,26 Finally, improved clinical and economic outcomes with primary prophylaxis (as opposed to secondary prophylaxis) are suggested by our observations. Approximately 10% of the study population received secondary prophylaxis, yet 94% of these patients had more than 1 clinical RF and did not receive primary prophylaxis. These patients had higher rates of FN than those who received primary prophylaxis. The ability to determine which patients may develop FN will help clinicians optimally target those appropriate for primary rather than secondary prophylaxis. RF analysis may be one way to do this. Continuing work in building a predictive risk model based on individual RFs could help. 27 Our findings align with prior research demonstrating costeffectiveness of primary prophylaxis among patients treated with intermediate-risk regimens. 28 Better patient Unfortunately, limitations related to the information available in claims studies prevented a thorough analysis of all clinical variables that affect the decision to use GCSF agents, such as chemotherapeutic dose and schedule, Eastern Cooperative Oncology Group performance status, laboratory results, or cancer diagnostic stage and subsequent treatment intent (ie, palliative care vs cure). Such limitations are common to retrospective studies. 14,15,24 Our observations suggest that physicians may link primary GCSF prophylaxis use to specific regimens or a particular RF more so than the number of individual RFs. This may be due to the guidelines' greater focus on specific chemotherapy regimens than clinical RFs and a combination of other factors. For example, some regimens are associated with an FN incidence in the higher end of intermediate risk myelosuppressive regimens, 14,15,24 individual RFs notwithstanding.
Given existing recommendations for prophylaxis, it is unclear why patients in the current study who had 1 or more RFs were not given GCSF. It is possible that the presence of a particular RF confers a greater likelihood of prophylaxis use than others. 15 In the current study, the majority (67%) of patients were aged older than 65 years, and the other most common RFs were prior surgery and baseline liver or kidney dysfunction. In fact, nearly all (98%) patients had at least 1 of these 3 top RFs. With each increase in the number of RFs, the unadjusted HR of FN events rose during all cycles and reached statistical significance at 3 and 4+ RFs for all cycles and 4 RFs for cycle 1. Yet, considering only number of RFs, prophylactic use did not rise proportionally for patients with 2 or more RFs overall.

FIGURE 3 FN-Related Coordination of Benefits-Adjusted Costs ($PPPM) by Primary Prophylactic Use
RFs and chemotherapy regimen may decrease the number of FN events and cycle delays and lower the FN-related health care burden. Reduced costs for prophylaxis may be achieved with the introduction of biosimilar agents. Further research should focus on whether primary GCSF prophylaxis improves outcomes in patients receiving non-curative chemotherapy by improving RDI and reducing early mortality.

ACKNOWLEDGMENTS
Writing, editorial support, and formatting assistance was provided by Caroline Jennermann, MS, an employee of Optum. must be constructed to identify them appropriately for each study.

DISCLOSURES
Determining the degree to which specific regimens or RFs contribute to risk of FN would require balancing prophylaxis and no prophylaxis cohorts on baseline characteristics and regimens to the greatest extent possible with a claims-based data source. 28 Unfortunately, for this observational study, primary drivers of FN risk, including chemotherapy dose data, were not available. Comparing outcomes across prophylaxis cohorts, balancing baseline characteristics and regimens, was outside the scope of these descriptive analyses but would be an important follow-up effort. Some analyses would be limited by low sample size, and residual confounding is possible from unobserved variables affecting care, such as dose reductions or delays, which were not captured or analyzed. Finally, generalizability may be limited by the specific time period and data source (commercial and Medicare Advantage enrollees) used. Despite understood limitations, realworld studies using claims data offer a real-world perspective and potentially large and diverse samples of patients treated in a variety of clinical settings.

Conclusions
This study demonstrated that the incidence of FN increased with the number of individual RFs observed among patients with cancer receiving intermediate-risk chemotherapeutic treatments between 2009 and 2019. However, use of primary prophylaxis did not increase with a rising number of RFs; thus, primary prophylactic use of GCSF remains suboptimal. Predictive consideration of RFs, regimens, and other patient-specific factors is needed to decide about appropriate use of GCSF in an individual patient. Administering appropriate prophylaxis based on individual FN identification for prophylactic use, based on RFs and select regimens, may produce better outcomes for patients as well as for payers. The main component of FN-related HCRU and cost is inpatient hospitalization, costs of which continue to grow. In the era of cost-effective biosimilar GCSF agents and the continuing COVID-19 pandemic, reevaluation of strict prior authorization policies and restricted access to GCSFs would be prudent.
Future research should focus on GCSF prophylaxis use based upon appropriate identification of RFs among individual patients and investigating whether primary prophylaxis strategies improve long-term outcomes in a population of patients in which the role of GCSF prophylaxis is controversial, for example, those not receiving curative chemotherapy regimens. Machine-learning predictive models are being developed with promising results. 29

LIMITATIONS
Although administrative claims data enable retrospective evaluations of treatment patterns, outcomes, and HCRU and costs, their purpose and design are for billing, rather than research. This imposes certain common limitations. First, a diagnosis code on a medical claim cannot be considered proof of disease because of the possibilities of incorrect coding or use of a code to indicate a rule-out criterion. Nevertheless, our analyses relied upon diagnosis codes to identify FN; thus, various definitions were tested for diagnostic robustness. We used strict ICD-9/10 code definitions to identify FN in the data, which may have increased the specificity but lowered sensitivity to identify all events and lowered rates as observed. In addition, lines of therapy are not explicitly captured by claims; thus, algorithms with various assumptions